Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy.

AIMS: 6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response. METHODS: Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis. RESULTS: During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 10(8) RBC) than in older children (600 pmol/8 × 10(8) RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 × 10(8) RBC), intermediate in wild-type patients and high (16468 pmol/8 × 10(8) RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 × 10(8) RBC was associated with an increased risk of hepatotoxicity. CONCLUSION: In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.

Population pharmacokinetics and pharmacogenetics of mycophenolic acid following administration of mycophenolate mofetil in de novo pediatric renal-transplant patients.

The objective was to develop a population pharmacokinetic-pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal-transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal-transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8-A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2-compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor influencing central volume of distribution and concomitant immunosuppressive medication and identified body weight and UGT2B7 802C>T genotype as individual factors influencing apparent oral clearance (CL/F) of MMF. CL/F in cyclosporine-MMF-treated patients was 33% higher than in tacrolimus-MMF-treated patients. The CL/F was significantly lower in patients with UGT2B7 802 C/C genotype compared with patients with UGT2B7 802 C/T and 802T/T genotypes, and this effect was independent of concomitant immunosuppressive medication or body weight. The population pharmacokinetic-pharmacogenetic model of mycophenolic acid was validated. Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal-transplant patients.

mRNA expression of MDR1 and major metabolising enzymes in human fetal tissues.

Metabolising enzymes and transport proteins are largely expressed in human tissues. They have major impact on drug disposition and effects. We studied mRNA expression of phase I and II metabolising enzymes and transporters in fetal tissues at different development stages. Hepatic, duodenal, renal and neurological fetal tissues were studied at 15, 27 and 42 weeks gestation and mRNA expression of 84 enzymes and transporters was analysed by with the RT(2) Profiler PCR array system. There was wide variability in gene expression between different samples. Independently from age, the highest expression levels were observed in the liver and the lowest in the brain for the majority of genes tested. There was significant increase in gene expression with age in duodenal and hepatic tissues.

Comparison of high-performance liquid chromatography and enzyme-multiplied immunoassay technique to monitor mycophenolic acid in paediatric renal recipients.

Therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) is recommended to guide immunosuppression. High-performance liquid chromatography with ultraviolet (HPLC-UV) or the enzyme-multiplied immunoassay technique (EMIT), used to measure mycophenolic acid (MPA) were compared in an exclusive paediatric renal transplant population. Twenty patients were included as part of the pharmacokinetics study of MMF, and 88 additional samples were drawn for TDM. Agreement between HPLC-UV and EMIT was assessed by the Bland-Altman method. With the two methods, pre-dose concentrations were not normally distributed. After logarithmic transformation, their mean was 0.79 +/- 1.16 microg ml(-1) and their mean difference was 0.34 +/- 0.16 microg ml(-1) [95% confidence interval (95%CI 0.30-0.38 microg ml(-1), with antilogarithmic values of these limits of 1.34-1.46 microg ml(-1)). Area under the curve (AUC)(HPLC) and AUC(EMIT) were normally distributed. Their mean was 52.42 +/- 25.91 mg x h/l and their mean difference was 15.22 +/- 8 mg x h/l (95%CI 11.99-18.45 mg x h/l), the Bland-Altman plot showing a bias proportional to the mean. Our data showed the absence of agreement between the HPLC and EMIT methods, with an average positive bias of 15% with the EMIT. Further studies are required to determine which method is best appropriate for TDM of MMF in children.